Cancer of the colon is the second most frequently diagnosed malignancy in the United States, as well as the second most common cause of cancer death. Colon cancer is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary treatment and results in cure in approximately 50% of patients. However, recurrence and metastases following surgery is a major problem and often is the ultimate cause of death.
Due to its proximity, cancer of the colon often metastasizes to the small intestine. The prognosis of the cancer spreading to the small intestine is related to the degree of penetration of the tumor through the bowel wall and the presence or absence of nodal involvement. These two characteristics form the basis for all staging systems developed for colon cancer. Various characteristics also assist in prognosticating colon cancer and its spread to the small intestines. For example, bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) and of carbohydrate antigen 19-9 (CA 19-9) also have a negative prognostic significance. However, age greater than 70 years at presentation is not a contraindication to standard therapies; acceptable morbidity and mortality, as well as long-term survival, are achieved in this patient population.
Cancer cells can also originate in the small intestine. However, this is a much rarer type of cancer.
Symptoms of cancer of the small intestine typically include pain or cramps in the middle of the abdomen, weight loss without dieting, a lump in the abdomen or blood in the stool.
Cancer of the stomach, also referred to as gastric cancer, also frequently metastasizes to the small intestine due to its proximity. This cancer is often difficult to diagnose in early stages and can be in the stomach for a long time, growing to a large size before symptoms arise. In the early stages of cancer of the stomach, an individual may experience indigestion and stomach discomfort, a bloated feeling after eating, mild nausea, loss of appetite or heartburn. In more advanced stages of stomach cancer, there may be blood in the stool, vomiting, weight loss or more severe pain.
Because of the frequency of these types of cancer (approximately 160,000 new cases of colon and rectal cancer per year alone), the identification of high-risk groups, the demonstrated slow growth of primary lesions and the better survival of early-stage lesions, screening for gastrointestinal cancers should be a part of routine care for all adults starting at age 50, especially those with first-degree relatives with colorectal cancer.
Procedures used for detecting, diagnosing, monitoring, staging, and prognosticating cancer of the colon, small intestine or stomach are of critical importance to the outcome of the patient. Patients diagnosed with early stage cancer generally have a much greater five-year survival rate as compared to the survival rate for patients diagnosed with distant metastasized cancers. New diagnostic methods which are more sensitive and specific for detecting early cancer of the stomach, small intestine and colon are clearly needed.
Patients with gastrointestinal cancers are closely monitored following initial therapy and during adjuvant therapy to determine response to therapy and to detect persistent or recurrent disease of metastasis. There is clearly a need for a cancer marker which is more sensitive and specific in detecting recurrence of these types of cancer.
Another important step in managing gastrointestinal cancers is to determine the stage of the patient's disease. Stage determination has potential prognostic value and provides criteria for designing optimal therapy. Generally, pathological staging of cancer is preferable over clinical staging because the former gives a more accurate prognosis. However, clinical staging would be preferred were it at least as accurate as pathological staging because it does not depend on an invasive procedure to obtain tissue for pathological evaluation. Staging of gastrointestinal cancers would be improved by identifying new markers in cells, tissues, or bodily fluids which could differentiate between different stages of invasion.
Accordingly, there is a great need for more sensitive and accurate methods for the staging of a cancer in a human to determine whether or not such cancer has metastasized and for monitoring the progress of a cancer in a human which has not metastasized for the onset of metastasis.
Thirteen colon specific genes and naturally occurring variants thereof, referred to as CSG1-13, are disclosed in U.S. Pat. No. 5,733,748 and WO 96/39541 for use as diagnostic markers in colon cancer. Some of these genes and polypeptides encoded thereby are also taught to be useful in determining if the colon cancer has metastasized.
It has now been found that galectin-4 and human carbonic anhydrase I serve as useful markers in the diagnosis of gastrointestinal cancer. These diagnostic markers are referred to herein generally as gastrointestinal specific genes or GSGs and more specifically as Cln114 (galectin-4) and Cln115 (human carbonic anhydrase I).
Cln114 was identified as human galectin-4 of 323 amino acids (translated molecular weight of 35918 Dalton). Galectin-4 belongs to the galectin family that include galectin-1 and galectin-3. Both galectin-3 and galectin-4 are found at high concentrations in intestinal extracts. Galectin-4 contains two beta-galactosidase-binding domains and localiazes mainly at sites of cell adhesion. Galectin-4 is a cytosolic protein but like galectin-1 and galectin-3 may be externalized by nonclassical secretory mechanisms and released from the cell. It is possible that galectin-4 is involved in cell adhesion via interaction with extracellular glycoconjugates. Galectin-4 has been suggested to play an important role in the maintenance of epithelial integrity and in the epithelial wound healing process (Huflejt et al. J. Biol. Chem. 1997 272(22):14294-303).
WO098/22139 describes differential expression of galectin-4 in human breast tumor cells. Other members of the galectin superfamily including galectin 8, 9, 10 and 10SV have been described as markers in the diagnosis of cancers including Hodgkin's disease, breast, ovarian, prostate, bone, liver, lung, pancreatic and splenic (see WO 98/15624).
In the present invention, methods are provided for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating gastrointestinal cancer via the gastrointestinal specific genes referred to herein as GSGs and more specifically as Cln114 and Cln115. For purposes of the present invention, GSG refers, among other things, to native protein expressed by the gene comprising a polynucleotide sequence of SEQ ID NO:1 or 3. Amino acid sequences encoded by the polynucleotides of SEQ ID NO:1 and 3 are depicted in SEQ ID NO:2 and 4, respectively. By “GSG” it is also meant herein polynucleotides which, due to degeneracy in genetic coding, comprise variations in nucleotide sequence as compared to SEQ ID NO:1 or 3, but which still encode the same protein. In the alternative, what is meant by GSG as used herein, means the native mRNA encoded by the gene comprising the polynucleotide sequence of SEQ ID NO:1 or 3, levels of the gene comprising the polynucleotide sequence of SEQ ID NO:1 or 3, or levels of a polynucleotide which is capable of hybridizing under stringent conditions to the antisense sequence of SEQ ID NO:1 or 3.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill in the art from the following description. It should be understood, however, that the following description and the specific examples, while indicating preferred embodiments of the invention are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following description and from reading the other parts of the present disclosure.